The nucleus of the solitary tract (NTS) is a functionally and anatomically heterogeneous group of cells that serves as a principle processing site regulating autonomic functions. Neurons of the NTS receive visceral sensory and gustatory signals and relay the information to visceral motor and other brain areas. Acetylcholine is a major autonomic neurotransmitter and the pre- and postsynaptic neuronal circuitry in the NTS receives a dense cholinergic innervation and expresses functional nicotinic acetylcholine receptors (nAChRs). Intravenous administration of nicotine in anesthetized rats decreases gastric motility and this effect could be significantly suppressed by bilateral vagotomy, indicating the involvement of functional nAChRs of the NTS and other nuclei of the brainstem dorsal vagal complex (DVC) in gastrointestinal reflexes. Despite its heterogeneity, the NTS contains discrete subsets of functionally-specific NTS cells. However, the pre- and postsynaptic cholinergic control of functionally-specific NTS pathways is unknown. Previous studies and recent preliminary data from this laboratory indicate that there are selective pre- and postsynaptic nicotinic effects on specific subsets of caudal NTS cells as defined by their morphology, cytochemical identity, afferent input, and axonal targets. Specifically, a robust enhancement of synaptic release of glutamate by nicotine has been observed in a subset of caudal NTS neurons (these will be referred to as presynaptically-responsive to nicotine) projecting to or through the key gastrointestinal control nucleus, the dorsal motor nucleus of the vagus, but not to the parabrachial nucleus, a primary target for the ascending autonomic and gustatory fibers to higher brain centers. Based on preliminary results, we hypothesize that specific subsets of caudal NTS cells with defined morphology, physiology, and brainstem projection or functional visceral target are differentially regulated by selective subtypes of presynaptic and somatodendritic nAChRs. Proposed experiments aim to: 1) relate nicotine's effects to the projection targets of subsets of caudal NTS neurons, identified using in vivo and ex vivo injections of retrograde tracers combined with patch-clamp electrophysiology (Aim 1); and 2) identify the cellular and synaptic mechanisms of underlying effects of nicotine in NTS brainstem slices (Aim 2). Understanding the mechanisms and pharmacology of nAChR subtypes underlying the effects of nicotinic agents on function- specific subsets of caudal NTS neurons will enhance our knowledge of the role of nAChRs in the processing and integration of gastric and other visceral information. This may result in the development of new therapeutic strategies for selective targeting of specific nicotine-responsive autonomic pathways (e.g., gastrointestinal). Results from the proposed studies could expand available therapeutic options aimed at improving digestive health and treatments of digestive disorders, such as obesity and anorexia. PUBLIC HEALTH RELEVANCE: Nicotine changes the activity of neurons in the brain that regulate the gastrointestinal system and are critical to feeding and digestion, but how this occurs is largely unknown. We have uncovered evidence of a powerful means for nicotine to regulate a small set of neurons that influence how the brain controls the gut, and these mechanisms are the topic of this proposal. The experiments here will point to new ways of using nicotinic mechanisms to modify functions of the gastrointestinal system associated with feeding.